Intestinal fluids contain several constituents with affinity for cyclodextrins that have the potential of displacing drugs from the cyclodextrin cavity by competition. In this study, the solubilizing capacity of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) for itraconazole was studied in presence of selected bile salts and phosphatidylcholine. Despite the fact that these competing agents significantly lowered the solubility of itraconazole in presence of cyclodextrins, the addition of concentrated solutions of these bile constituents to a solution containing itraconazole solubilized by HP-β-CD did not result in precipitation, even at bile salt and phospholipid concentrations where itraconazole precipitation would be anticipated based on solubility studies. This phenomenon was further investigated in more dynamic conditions via in vitro transfer studies, mimicking the gastrointestinal transfer of HP-β-CD solutions saturated with itraconazole. Intestinal supersaturation upon transfer was observed for all conditions tested and a concentration dependent impact of bile salts and phospholipids on the precipitation behavior of itraconazole was demonstrated: high concentrations of bile salts and phospholipids generated the highest degrees of supersaturation shortly after the transfer step but also resulted in stronger itraconazole precipitation at later time points. These findings demonstrate the possible impact of the variable intestinal fluid composition on the behavior of cyclodextrin containing formulations.
Keywords: Biorelevant media; Cyclodextrin; Gastrointestinal transfer; Itraconazole; Precipitation; Supersaturation.
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